Technical Field
[0001] The present invention relates to a method of manufacturing a microneedle.
Background Art
[0002] Percutaneous absorption has been known as one of the methods for administering a
drug by permitting it to permeate through the skin. In this method, a liquid or gel
of the drug is applied on the surface of a living body such as the skin or mucous
membrane.
[0003] This method is noninvasive, and makes it possible to simply administer the drug without
giving pain to the human body. However, the applied drug is liable to be removed by
perspiration or external contact. Another problem may arise in terms of safety since
skin failure occurs by long-term administration. In addition, the drug is hardly absorbed
in the body merely by applying it on the surface of the body when the drug to be administered
has a high molecular weight or the drug is water soluble, and percutaneous absorption
of such drug is difficult.
[0004] Accordingly, a noticed method is to directly inject the drug beneath the skin by
perforating the skin using a microneedle array having many needles of micron order
in order to permit the drug to be efficiently absorbed into the body. This method
enables simple subcutaneous administration without using any special devices (see
U.S. Patent No. 6,183,434).
[0005] The microneedle used in this method is required to have sufficient fineness and point
angle for perforating the skin, and a sufficient length for permitting the drug solution
to be permeated under the skin. Consequently, it is thought to be desirable that the
needle diameter is from several 1 µm to 100 µm, and the needle length is selected
so that the needle penetrates through corneum that is an outermost layer of the skin
while the needle does not reach a nerve layer, or specifically from scores of µm to
hundreds of µm. The material constituting the needle is required to be harmless to
the human body even when the needle is broken and left behind in the body. Materials
considered to be promising include medical use silicone resins and biocompatible resins
such as maltose, polylactate and dextran resins (see Jpn. Pat. Appln. KOKAI Publication
No.
2005-21677).
[0006] For mass production of needles having such a fine structure with a low production
cost, transcription molding methods represented by injection molding method, imprint
method and casting method are effective. However, a mold having inversed projections
and recesses of a desired shape is necessary for molding by any of the above-mentioned
methods, and a quite complicated production process is required for forming a structure
that is necessary to have a high aspect ratio (a ratio of the height or depth to the
diameter of the structure) and an acute tip as the microneedle.
[0007] In a proposed method of manufacturing the microneedle, the tip of the needle is sharpened
by anisotropic wet etching of a single crystal material such as a silicon wafer by
taking advantage of a difference in etching rates between respective crystal orientations
of the singe crystal. However, a strict control of the anisotropic wet etching time
is necessary for sharpening the tip of the needle, and a high degree of processing
technology becomes necessary (Jpn. Pat. Appln. KOKAI Publication No.
2002-79499).
[0008] Other proposed methods include controlling the point angle of the needle by changing
the light exposure value while an exposure mask is moved (see Jpn. Pat. Appln. KOKAI
Publication No.
2005-246595), or combining wet etching using a chemical solution and plasma etching (see Jpn.
Pat. Appln. KOKAI Publication No.
2002-239014).
[0009] Another method of manufacturing microneedles to form a microneedle patch includes
the steps of forming tips of the microneedles by isotropic etching under a resist
mask, and forming microneedles with a desired height by anisotropic etching (see Jpn.
Pat. Appln. KOKAI Publication No.
2005-199392).
[0010] However, the above-mentioned manufacturing methods involve a problem in the cost
and time since the methods include many complicated steps of forming a thermal oxide
layer, applying a resist, forming a mask pattern by photolithography, applying isotropic
etching, applying anisotropic etching, removing a sidewall deposit layer, and applying
gradient etching.
[0011] While the microneedle is required to be uniformly formed particularly with respect
to the height since the microneedle should reliably arrive at body tissues such as
the epidermis, it is difficult to form the microneedle with high accuracy by the above-mentioned
methods.
[0012] A special exposure apparatus that is not usually used, a high precision machining
technique and a complicated manufacturing process are often needed for satisfying
the structural requirement of the microneedle, since a high aspect ratio as well as
sharpening the tip are necessary in the conventional methods for manufacturing the
microneedle. It is another problem that stripped pieces of the mask contaminate around
the mask as etching advances.
Disclosure of Invention
[0013] An object of the invention is to provide a method of manufacturing a needle capable
of readily controlling the point angle and height without using any complicated manufacturing
process or special manufacturing apparatus.
[0014] The invention provides a method of manufacturing a microneedle characterized by comprising
the steps of: forming an island etching mask having thickness distribution on a substrate;
and processing the substrate into a needle by taking advantage of a difference in
etching rates between the etching mask and the substrate.
[0015] In the invention, it is preferable to form an array of etching masks on the substrate.
[0016] The invention may comprise the steps of: providing a recess having depth distribution
on the substrate; and forming the island etching mask having thickness distribution
so as to cover at least a part of the recess.
[0017] In the invention, the etching mask may be formed so as to cover the recess and a
part of a periphery of the recess, or may be formed so as to cover an entire surface
of the substrate including the recess.
[0018] In the invention, an opening may be provided at a position corresponding to the recess
of the etching mask, or the opening may be formed so as to be displaced from the recess.
[0019] The invention may comprise the steps of: forming an island etching mask on the substrate;
deforming the etching mask so as to have thickness distribution; and processing the
substrate into a needle by taking advantage of a difference in etching rates between
the etching mask and the substrate.
[0020] In the invention, the island etching mask formed on the substrate is deformed so
as to have thickness distribution by allowing the etching mask to reflow.
[0021] In the invention, the island etching mask may be formed on the substrate by ejecting
a droplet prepared by dissolving an etching mask material in a solvent or by ejecting
a droplet prepared by heating and melting the etching mask material, and the etching
mask may be deformed so as to have thickness distribution by allowing the solvent
to evaporate or by allowing the etching mask material to solidify.
[0022] The invention may comprise the steps of: forming a hole on the substrate; filling
the hole with a filler; forming an island etching mask on a side of the substrate
where the hole is formed; deforming the etching mask in a thickness direction; etching
the substrate to process into a needle; and removing the filler.
[0023] The invention may comprise the steps of: forming a hole on the substrate; forming
an island etching mask on a side of the substrate opposed to the side where the hole
is formed; deforming the etching mask in a thickness direction; and etching the substrate
to process into a needle.
[0024] In these methods, the hole may be a non-penetrated hole or a penetrated hole. Further,
a position of the etching mask may be aligned with a position of the hole, or a position
of the etching mask may be displaced from a position of the hole.
[0025] In the invention, the etching mask may be formed into a shape having a periphery
a part of which is inwardly depressed.
[0026] In the invention, an etching selectivity ratio defined by dividing the etching rate
of the substrate by the etching rate of the etching mask is preferably set to 1 or
more and 100 or less. In addition, an etching condition may be changed so that an
etching selectivity ratio is changed on the way of etching.
[0027] The invention may comprise the steps of: forming a resist layer on the substrate;
exposing the resist layer with light using any one of exposure through a mask using
a halftone dot pattern, exposure through a mask using a gray scale pattern, multiple
laser exposure and inclined exposure; developing the resist layer to form the island
etching mask having thickness distribution on the substrate; and processing the substrate
into a needle by taking advantage of the difference in etching rates between the etching
mask and the substrate.
[0028] In the invention, anisotropic etching is used for the etching. The anisotropic etching
includes ion etching, reactive ion etching, ion-beam etching and reactive ion-beam
etching.
[0029] In the invention, after the microneedle is formed, the microneedle may be subjected
to isotropic etching.
[0030] In the invention, a replica mold for manufacturing a microneedle may be manufactured
by transcription using the manufactured microneedle as a master mold. In this case,
the transcription can be performed by using a plated metal, resin or ceramic.
[0031] The invention also includes a microneedle manufactured by the above-mentioned method.
The invention also includes a microneedle manufactured by using the replica mold for
manufacturing the microneedle. The microneedle of the invention is preferably formed
of a biocompatible material.
Brief Description of Drawings
[0032]
FIG. 1 shows cross-sectional views showing a method of manufacturing a microneedle
of the invention.
FIG. 2 shows examples of needles which can be formed by the manufacturing method according
to the invention.
FIG. 3 shows examples of needles which can be formed by the manufacturing method of
the invention.
FIG. 4 shows examples of needles which can be formed by the manufacturing method of
the invention.
FIG. 5 shows cross-sectional views showing a method of manufacturing the microneedle
of the invention.
FIG. 6 shows an example of a needle which can be formed by the method of manufacturing
the microneedle according to the invention.
FIG. 7 shows an example of a needle which can be formed by the method of manufacturing
the microneedle according to the invention.
FIG. 8 shows examples of needles which can be formed by the method of manufacturing
the microneedle according to the invention.
FIG. 9 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 10 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 11 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 12 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 13 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 14 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 15 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 16 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 17 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 18 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 19 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 20 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 21 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 22 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 23 shows cross-sectional views showing steps of a method of manufacturing a microneedle
using a transcription process according to the invention.
FIG. 24 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
FIG. 25 shows cross-sectional views showing a method of manufacturing a microneedle
according to the invention.
Best Mode for Carrying Out the Invention
[0033] A method of manufacturing a microneedle according to an embodiment of the invention
will be described with reference to FIGS. 1a to 1f.
<Process for providing a recess having depth distribution on a substrate>
[0034] A recess having depth distribution is formed on a substrate at the position corresponding
to the position for forming the needles.
[0035] Any materials may be used for the substrate as long as they can be processed by wet
etching, plasma etching and blast treatment. Specific examples of the material include
silicon, a metal such as aluminum and stainless steel, and a synthetic resin such
as polycarbonate, polystyrene, acrylic resin and fluorinated resin.
[0036] Examples of the method for forming the recess include wet etching, laser machining,
reactive ion etching and focused ion beam. Since the final shape and diameter of the
needle depend on the shape and diameter of the recess formed, the shape of the recess
is determined depending on the shape of the desired needle.
[0037] For example, the point angle and height of the needle that is finally manufactured
may be controlled by controlling the shape of the bottom of the recess. The point
angle tends to be sharpened when the bottom of the recess has an acute angle, while
the height of the needle tends to be increased when the recess is deep.
[0038] A case of providing the recess by etching will be described. First, etching mask
is formed on the substrate (FIG. 1a).
[0039] The etching mask may be formed using a resist, a hard mask having a pattern of opening
on a metal film, or a metal film, an organometallic film, a silicone oxide film or
silicon nitride film directly formed on the substrate by CVD (chemical vapor deposition)
or PVD (physical vapor deposition). Alternatively, a silicon oxide film formed by
thermal oxidation may be used when the substrate is silicon.
[0040] When needles are to be formed, it is possible to form an array having any number
of needles at any pitch by appropriately designing a pattern layout of the etching
mask to be formed.
[0041] A recess 103 having depth distribution is formed by etching the substrate exposed
out of the etching mask (FIG. 1b). The etching mask 102 is removed after the recess
is formed.
[0042] In this case, the shape of the bottom of the recess may be determined by the difference
in the etching rate depending on the crystal orientation of the substrate or by the
etching selectivity ratio between the etching mask and substrate. As described above,
the point angle and height of the needle to be finally manufactured may be controlled
by controlling the shape of the bottom of the recess.
<Process for forming an etching mask having thickness distribution>
[0043] An etching mask having thickness distribution is then formed on the substrate so
that the mask covers at least a part of the recess. For example, if an etching mask
is formed over the entire surface of the substrate, the etching mask 104 filled in
the recess 103 has thickness distribution (FIG. 1c). Accordingly, the etching mask
104 is not necessarily patterned.
<Process for etching the substrate>
[0044] The entire surface of the substrate 101 on which the etching mask 104 is formed is
etched to form a microneedle 106 (FIGS. 1d and 1e). When silicon is used for the substrate
101, the substrate is subjected to anisotropic etching using a fluorine-based gas.
[0045] When the etching starts from the state shown in FIG. 1c, the etching mask 104 is
etched with the same thickness on the entire surface, the top surface of the substrate
101 is exposed, and the etching mask 104 having thickness distribution is left behind
only on the recess 103. When the etching further advances from this state, the substrate
101 having a higher etching rate is etched more than the etching mask 104. The point
angle of the needle can be controlled by the etching selectivity ratio between the
etching mask 104 and substrate 101 (the ratio of the etching rate of the etching mask
to the etching rate of the substrate). The point angel of the needle becomes sharp
with an increased height when the etching selectivity ratio is high. The point angle
of the needle becomes dull with a decreased height when the etching selectivity ratio
is low.
[0046] As shown in FIG. 1d, if the etching is stopped at the state having a remaining etching
mask and the remaining etching mask is stripped off, a needle having a recess corresponding
to the shape of the bottom of the recess at the tip may be manufactured. The needle
having such a recess at the tip is favorable for use in, for example, sampling the
blood and injecting a drug solution.
<Transcription of microneedle>
[0047] By using the microneedle 106 manufactured as shown in FIG. 1e as a master mold, a
replica mold 107 may be manufactured (FIG. 1f). Any materials may be used as the material
of the replica mold 107 as long as they have appropriate shape adaptability and hardness,
and examples thereof include plated metals and molding resins such as organic silicones.
[0048] The metal plating method will be described below. A metal layer is uniformly formed
by plating over the entire surface of the microneedle 106 used as the master mold.
Then, the microneedle 106 used as the master mold is removed to form a replica mold
107 made of the metal.
[0049] Although the thickness of the metal film formed is not limited, it is preferably
twice or more as thick as the height of the needle. The type of the metal is not particularly
limited, and nickel, copper and various alloys may be favorably used.
[0050] Ceramics and resins may be used other than the metal materials. Examples of the method
for depositing the film include plating as well as plasma deposition, sputtering,
CVD, evaporation, sintering and casting.
[0051] Subsequently, the replica mold 107 is used for transcription to various materials.
The microneedle is replicated by imprinting, hot-embossing, injection molding or casting
with the use of the replica mold 107. Although the material of the replicated product
is not particularly limited, a biocompatible microneedle may be formed by using a
biocompatible material such as a medical use silicone resin, maltose, polylactic acid,
dextran or chitin-chitosan.
<Modified example of FIG. 1>
[0052] The etching mask is formed on the entire surface of the substrate in FIG. 1c, but
varying the pattern of the etching mask enables to manufacture a microneedle having
various shapes. Embodiments in which the pattern of the etching mask is varied will
be described.
[0053] As shown in FIG. 2a, a pattern of an etching mask 201 that covers the recess 103
and a part of the periphery of the recess 103 may be formed. In this case, as shown
in FIG. 2b, a microneedle 202 having a reinforced bottom part may be manufactured
by etching.
[0054] Since the bottom of the microneedle receives large stress when the needle is stabbed,
an effect that the needle is hardly broken in stabbing may be obtained if the needle
has the reinforced bottom part.
[0055] An opening 301 that corresponds to the center of the recess 103 may be provided on
the etching mask 104 formed on the entire surface of the substrate as shown in FIGS.
1 and 3a. Since the center of the bottom of the recess 103 corresponding to the opening
301 of the etching mask 104 is etched faster as shown in FIG. 3b, a microneedle 302
having a hollow part is formed. The microneedle 302 having the hollow part has a shape
favorable for sampling of the blood and injection of a drug solution.
[0056] The center of the recess 103 and the center of the opening 301 may be displaced from
each other within the area of the recess 103. The opening 301 may be provided at a
position where no recess 103 is formed.
[0057] The height of the microneedle may be readily controlled by changing the thickness
of the etching mask. The height of the needle manufactured tends to be larger as the
thickness of the etching mask is larger.
[0058] As shown in FIG. 4a, a thick etching mask 401 may be formed only at the position
corresponding to the recess 103. In this case, as shown in FIG. 4b, a microneedle
whose body is a round column instead of being a cone and which is sharpened only at
the tip can be produced by etching. In this manner, it is possible to control the
height of the microneedle irrespective of the depth of the recess 103 provided in
advance.
[0059] The method of manufacturing a microneedle according to another embodiment of the
invention will be described below with reference to FIGS. 5a to 5d.
<Process for forming etching mask on the substrate>
[0060] First, an etching mask 102 is formed on the substrate 101 (FIG. 5a).
[0061] Any materials may be used for the substrate as long as they can be processed by etching
such as plasma etching, and any materials suitable for the processing method may be
selected appropriately. Specific examples include silicon, a metal material such as
aluminum and stainless steel, and a synthetic resin such as polycarbonate, polystyrene,
acrylic resin and fluorinated resin.
[0062] The preferred material of the etching mask is required to be adhesive to the substrate,
and to have a lower etching rate than the etching rate of the substrate in the etching
process described below.
[0063] The method for forming the etching mask is required to be able to uniformly form
the etching mask on the substrate, and specific examples of the method include CVD
(chemical vapor deposition), PVD (physical vapor deposition), spray coating and ejection
of droplets.
[0064] Any known methods may be appropriately used for forming the pattern of the etching
mask. For example, usable methods include a method of exposure and development (where
the pattern is controlled by a photomask used) and a method of ejecting a droplet
(where the droplet is ejected into the pattern only).
[0065] Since the diameter of the needle manufactured depends on the diameter of the etching
mask formed, the diameter of the etching mask is adjusted according to the diameter
of the desired needle.
[0066] An array of etching masks may be formed. Manufacture of a microneedle array is possible
by forming the array of the etching masks. The pitch between the needles and the number
of the needles may be controlled by adjusting the pattern layout of the etching mask.
<Process for deforming the etching mask so as to have thickness distribution>
[0067] Next, the etching mask is deformed so as to have thickness distribution (FIG. 5b).
[0068] Thin portions of the etching mask are removed faster than thick portions of the etching
mask in the etching process described below. Accordingly, the time needed for removing
the mask may be controlled by allowing the etching mask to have thickness distribution.
Since the substrate is being etched simultaneously, etching of the portion of the
substrate corresponding to the portion of the removed mask advances as the mask is
removed.
[0069] When the thickness of the periphery of the etching mask is reduced relative to the
thickness at the central portion of the etching mask, and the thickness of the etching
mask is made to continuously change from the periphery to the central portion of the
etching mask, the mask is gradually removed from the periphery of the etching mask
as etching advances. Thus, a needle having a taper angle depending on the etching
selectivity ratio between the substrate and etching mask (the ratio of the etching
rate of the substrate to the etching rate of the etching mask) can be manufactured.
[0070] Since the time required for removing the mask is controlled by allowing the etching
mask to have thickness distribution, the point angle and the height of the needle
manufactured may be controlled in the etching process described below. When the mask
is etched until the etching mask is eliminated under the same etching condition, the
height of the needle manufactured increases as the thickness of the initial etching
mask is larger.
[0071] The etching mask may be reflowed for deforming the etching mask so as to have thickness
distribution. When the etching mask is made to reflow by heating, the thickness of
the etching mask smoothly changes owing to surface tension. Thus, the thickness of
the etching mask at the periphery is reduced relative to the thickness at the central
portion of the etching mask so that the thickness of the etching mask continuously
changes from the periphery to the central portion of the etching mask.
[0072] The thickness distribution of the etching mask is determined by the reflow condition.
Accordingly, when plural etching masks are provided on the substrate in particular,
the thickness distribution of the etching masks is made uniform, thereby plural needles
may be manufactured in one step with high precision.
[0073] The thickness and the thickness distribution of the etching mask after reflow may
be adjusted by adjusting the initial thickness of the etching mask and heating temperature.
[0074] In performing reflow, the substrate may be heated. The heating method is not particularly
limited. For example, the substrate may be heated using a heating device such as an
oven or a hot plate.
[0075] Alternatively, when the etching mask is formed by ejecting droplets prepared by dissolving
a mask material in a solvent or by ejecting droplets prepared by melting the mask
material with heating with the use of the droplet ejecting method, the etching mask
may be deformed so as to have thickness distribution by allowing the solvent to evaporate
or by allowing the mask material to solidify. Even in these methods, the thickness
of the etching mask smoothly changes owing to surface tension. Consequently, the thickness
of the etching mask may be reduced at the periphery relative to the thickness at the
central portion of the etching mask so that the thickness of the etching mask continuously
changes from the periphery to the inner portion of the etching mask.
[0076] The etching mask may be formed in an arbitrary shape within the range of accuracy
of ejection of droplets when the etching mask is formed by ejecting the droplets.
[0077] The thickness distribution of the etching mask is determined by the evaporation condition
of the solvent or solidification condition. Accordingly, when plural etching masks
are formed on the substrate, the thickness distribution of each etching mask may be
uniform, thereby plural needles may be manufactured with high precision in one step.
[0078] When the solvent is evaporated or the mask material is solidified, the substrate
is heated or placed under a reduced pressure, or heated under a reduced pressure.
The evacuation method and heating method are not particularly limited, and a heating
device such as an oven or a hot plate operated under a reduced pressure may be used.
<Process for etching>
[0079] The entire substrate on which the etching mask has been formed is further etched
(FIG. 5c) to manufacture the microneedle (FIG. 5d).
[0080] The etching method may be any methods as long as the method uses anisotropic etching
in which the etching rate of the substrate is different from the etching rate of the
etching mask, and any known methods may be appropriately used. For example, dry etching
with a dry etching apparatus using discharge methods such as RIE, magnetron RIE, ECR,
ICP, NLD, microwave and helicon wave.
[0081] When the thickness of the etching mask is continuously changed from the periphery
to the central portion of the mask so that the thickness at the periphery of the etching
mask is smaller than the thickness at the central portion of the etching mask, the
etching mask is gradually removed from the periphery of the etching mask as etching
advances. Consequently, microneedles having a taper angle depending on the etching
selectivity ratio between the substrate and etching mask (the ratio of the etching
rate of the substrate to the etching rate of the etching mask) may be manufactured.
[0082] The etching mask may be inwardly depressed at least at a part of the periphery. Examples
of the shape of the etching mask having a periphery that is inwardly depressed at
least at a part thereof include a cross-shaped etching mask 202 formed on the substrate
201 as shown in FIG. 6a, or an etching mask 203 having a circular bottom a part of
which is inwardly depressed and formed on the substrate 201 as shown in FIG. 7a. Other
examples include a star-like shape in which the bottom has an arbitrary number of
apexes, which are connected with continuous straight lines or curved lines.
[0083] When at least a part of the periphery of the etching mask is inwardly depressed,
a depression is formed on the sidewall of the needle as shown in FIGS. 6B and 7B after
etching, thereby the surface area of the needle may be increased. Consequently, a
needle having a shape suitable for holding and injecting a drug solution may be manufactured.
[0084] Since the taper angle of the needle is determined by the etching selectivity ratio
between the substrate and etching mask as described above, the taper angle and point
angle of the needle may be designed and manufactured without limiting the material
of the substrate to a single crystal material.
[0085] The point angle of the needle can be controlled by the etching selectivity ratio
of the substrate to the mask. The point angle of the needle tends to be sharpened
with a larger height of the needle when the etching selectivity ratio is higher, while
the point angle tends to be dull with a smaller height of the needle when the etching
selectivity ratio is lower.
[0086] Since the mask is gradually removed and the needle is formed by completely removing
the mask after the mask has been finally converged into a fine area, a needle having
a sharp tip may be manufactured without being contaminated with stripped etching mask.
[0087] The etching may stopped at a state that the etching mask is still left behind (FIG.
5c), and then the mask may be stripped off. A needle having a flat portion only at
the tip of the needle may be manufactured. Such needle is able to reduce break of
the tip when the needle is stabbed.
[0088] The etching condition may be changed so that the etching selectivity ratio of the
substrate to the etching mask is changed on the way of etching.
[0089] Since the taper angle is determined by the etching selectivity ratio as described
above, a needle having a taper angle that changes stepwise may be manufactured by
changing the etching condition on the way of etching.
[0090] The etching selectivity ratio that is a value provided by dividing the etching rate
of the substrate to be etched by the etching rate of the etching mask is preferably
from 1 or more to 100 or less. An etching selectivity ratio from 5 or more to 50 or
less is particularly preferable for precisely transcribing the shape of the etching
mask to the substrate.
[0091] However, the etching selectivity ratio is not limited to the above-mentioned range,
and may be appropriately changed depending on the desired taper angle of the needle.
For example, a very large selectivity ratio (100 or more) may be used when the etching
condition is changed on the way of etching.
[0092] When etching starts with a smaller etching selectivity ratio and the etching selectivity
ratio is increased thereafter, the bottom of the needle becomes to have a gentle taper
angle so that a needle having a reinforced shape at the bottom where the needle receives
large stress in stabbing may be manufactured. Such a needle exhibits an effect that
makes the needle hardly broken in stabbing (FIG. 8a).
[0093] When the etching selectivity ratio is made very high, the sidewall of the needle
may be made to have an approximately vertical angle since the etching rate of the
substrate is quite higher relative to the etching rate of the etching mask. Accordingly,
a needle having a high aspect ratio may be manufactured while the diameter of the
bottom part is kept constant (FIG. 8b). In particular, in the case of an array having
arranged needles, a high aspect ratio is effective since the needles may be densely
disposed.
[0094] The etching condition may be changed with a combination of the etching conditions.
The combination of changes of the etching condition permits a needle having a gentle
slope at the bottom and a high aspect ratio to be manufactured (FIG. 8c).
[0095] As described above, the needle can be manufactured by a simple manufacturing process
in which the point angle and the height of the needle can be readily controlled.
[0096] The method of manufacturing a needle having a hole or penetrated hole will be described
below with reference to FIGS. 9 and 10.
<Process for forming a hole on the substrate>
[0097] First, a hole 401 is formed on the substrate (FIG. 9a). If the hole 401 is provided
at a position corresponding to the etching mask of the substrate 101 in advance, a
hollow needle may be manufactured. The needle having such a shape is favorable, for
example, for sampling the blood and for injecting a drug solution.
[0098] Any known methods may be appropriately used for forming the hole 401 on the substrate
depending on the shape, dimension and degree of integration of the needle. Example
of the method include deep etch by etching, laser processing and other precise machining.
[0099] A hole 501 that penetrates the substrate may be formed (FIG. 10a). A needle having
a penetrated hole may be manufactured by providing the hole 501 that penetrates the
substrate.
<Process for filling the hole with a filler>
[0100] Next, the hole 401 or 501 provided on the substrate is filled with a filler 402 or
502 (FIG. 9b or 10b).
[0101] Any filler may be used as long as it is able to fill the hole having a size from
several 1 µm to hundreds of µm. Examples of the filler include a metal material such
as Ni, silicone and a heat resistant resin.
[0102] Any known methods may be appropriately used for filling with the filler. Examples
of the method include plating such as electroplating and filling the hole with a molten
material.
<Process for forming an etching mask having thickness distribution at a portion corresponding
to the hole and process for etching>
[0103] Next, an etching mask having thickness distribution is formed at the portion corresponding
to the hole (the etching mask 403 or 503), and etching is performed (FIG. 9c or 10c).
[0104] These processes may be implemented by the same method as described above.
<Process for removing the filler>
[0105] The needle 404 or 504 is provided by removing the filler 402 or 502 (FIG. 9d or 10d).
[0106] Any methods may be available as long as the filler can be removed without heavily
damaging the substrate. For example, the filler may be dissolved by using various
etching solutions or solvents suitable for the selected filler.
[0107] Another embodiment of a method of manufacturing the needle by providing a penetrated
hole will be described below with reference to FIG. 11.
<Process for forming a hole on the substrate>
[0108] First, a non-penetrated hole 601 is formed on the substrate (FIG. 11a). The substrate
used and the method for forming the hole are the same as described above.
<Process for forming an etching mask on a side of the substrate opposed to the side
where the hole is provided, and for deforming the etching mask so as to have thickness
distribution>
[0109] Next, an etching mask 602 is formed on the side of the substrate opposed to the side
where the hole 601 is provided, and the etching mask 602 is deformed so as to have
thickness distribution (FIG. 11b). The method for forming the etching mask and for
deforming the mask so as to have thickness distribution is the same as described above.
[0110] When the etching mask 602 corresponding to the hole is formed on another side of
the substrate opposed to the side where the hole is provided, a needle having a penetrated
hole can be manufactured without filler.
<Process for etching>
[0111] Next, etching is performed to manufacture a needle 603 having a penetrated hole (FIG.
11c). This process can also be performed as described above.
[0112] A hollow needle is produced by the method as described above. Such a hollow needle
has a shape favorable for sampling the blood and for injecting a drug solution.
<Modified example of FIG. 9>
[0113] The depth of the hole is approximately the same as the depth of etching in FIG. 9,
but the relation between the depth of the hole and the depth of etching can be appropriately
adjusted.
[0114] FIGS. 12a to 12d show an example in which the substrate is etched deeper than the
depth of the hole.
[0115] FIGS. 13a to 13d show an example in which the substrate is etched shallower than
the depth of the hole.
<Modified example of FIG. 10>
[0116] The center of the hole and the center of the etching mask are aligned with each other
in FIG. 10, but the center of the hole and the center of the etching mask may be slightly
displaced from each other.
[0117] FIGS. 14a to 14d show an example in which the center of the hole and the center of
the etching mask are slightly displaced from each other. An opening having an inclined
plane is formed at the tip of the needle in this example.
<Modified example of FIG. 11>
[0118] The center of the hole and the center of the etching mask formed on the opposite
side of the substrate are aligned with each other in FIG. 11, but the center of the
hole the center of the etching mask formed on the opposite side of the substrate may
be slightly displaced from each other.
[0119] FIGS. 15a to 15d show an example in which the center of the hole and the center of
the etching mask are slightly displaced from each other. An opening having an inclined
plane is formed at the tip of the needle also in this example.
<Modified example of FIG. 9>
[0120] The center of the hole and the center of the etching mask are aligned with each other
in FIG. 9, but the center of the hole and the center of the etching mask may be slightly
displaced from each other.
[0121] FIGS.16a to 16d show an example in which the center of the hole and the center of
the etching mask are slightly displaced from each other. An opening having an inclined
plane is also formed at the tip of the hollow needle in this example.
<Modified example of FIG. 16>
[0122] The depth of the hole is approximately the same as the depth of etching in FIG. 16,
but the relation between the depth of the hole and the depth of etching can be appropriately
adjusted.
[0123] FIGS. 17a to 17d show an example in which the substrate is etched deeper than the
depth of the hole.
[0124] FIGS. 18a to 18d show an example in which the substrate is etched shallower than
the depth of the hole.
<Modified example of FIG. 10>
[0125] The center of the hole and the center of the etching mask are aligned with each other
in FIG. 10, but the hole and the etching mask may be displaced from each other so
that they are not overlapped.
[0126] FIGS. 19a to 19d show an example in which the hole and the etching mask are displaced
from each other so that they are not overlapped. The penetrated hole is formed remote
from the position of the needle in this example.
<Modified example of FIG. 11>
[0127] The center of the hole is aligned with the center of the etching mask formed on the
opposed side of the substrate, but the hole and the etching mask may be displaced
from each other so that they are not overlapped.
[0128] FIGS. 20a to 20c show an example in which the hole and the etching mask are displaced
from each other so that they are not overlapped. The penetrated hole is formed remote
from the position of the needle also in this example.
<Modified example of FIG. 20>
[0129] Although the non-penetrated hole is formed in FIG. 20, a penetrated hole may be provided
when the hole and the etching mask are displaced from each other so that they are
not overlapped.
[0130] FIGS. 21a to 21c show an example in which the penetrated hole and the etching mask
are displaced from each other so that they are not overlapped. The penetrated hole
is formed remote from the position of the needle also in this case.
[0131] In any of the above-mentioned examples, isotropic etching may be further applied
after forming the needle. FIGS. 22a to 22c show an example in which the needle once
formed is subjected to isotropic etching. When the needle in FIG. 22a is subjected
to isotropic etching, the entire shape of the needle is uniformly contracted by a
given length as shown in FIG. 22b. Consequently, the bottom of the needle is rounded
while the tip of the needle is sharpened as shown in FIG. 22c. The isotropic etching
performed in this manner can adjust the shape of the needle such that the needle is
made to be ready for stabbing and hardly broken.
<Transcription of needle>
[0132] Transcription of the needle will be described below with reference to FIG. 23.
[0133] A replica mold 703 is formed by using the microneedle 701 manufactured by the above-mentioned
method as a master mold.
[0134] First, the replica mold 703 is formed on the surface on which the needle 701 is formed
(FIG. 23a).
[0135] Although the material of the replica mold 703 is not particularly limited, it is
selected in terms of shape adaptability for serving as the replica mold, transcription
ability in the transcription process described below, durability and releasing ability.
For example, nickel may be used as the material of the replica mold 703. In this case,
the method of forming the nickel film includes plating, PVD and CVD.
[0136] Then, the replica mold 703 is separated from the needle 701 (FIG. 23b).
[0137] As the method of separating the replica mold 703 from the needle 701, separation
with physical peeling force or selective etching may be used.
[0138] Next, the replica mold 703 is filled with a needle material (FIG. 23c).
[0139] Although the needle material is not particularly limited, a biocompatible needle
may be formed by using a medical silicone resin, maltose, polylactic acid, dextran,
chitin or chitosan as a biocompatible material.
[0140] Although the method for filling with the needle material is not particularly limited,
imprinting, hot-embossing, injection molding, extrusion molding or casting may be
favorably used in terms of productivity.
[0141] Next, the needle material is released from the replica mold 703 to provide a needle
704 formed by transcription molding (FIG. 23d).
[0142] For improving peeling property from the replica mold 703, a release layer (not shown)
for enhancing releasing effect may be formed on the surface of the replica mold 703
prior to filling with the needle material.
[0143] As the release layer, widely known fluorinated resins, for example, may be used.
As the method for forming the release layer, PVD, CVD, spin coating or dip coating
may be favorably used.
[0144] The transcription of the needle can be performed as described above. Since mass production
of needles can be implemented using the same replica mold by manufacturing a replica
mold having a high mechanical strength which is integrally molded, the needles may
be produced under low production cost with high productivity.
[0145] Other embodiments of the invention will be described below with reference to FIGS.
24 and 25.
[0146] FIGS.24a to 24d show a process for manufacturing a microneedle of this embodiment,
and FIGS. 24e and 24f show a process for manufacturing a replica mold using the microneedle
as a master mold.
[0147] First, as shown in FIG. 24a, a negative resist is applied to the surface of a substrate
13 to form a resist layer 12.
[0148] Then, the resist layer 12 is exposed into a pattern of the microneedles by photolithography
using a mask 15. The mask 15 is this embodiment is formed by providing a needle pattern
array in which needle-shaped unit masks 16 schematically shown in FIG. 25b are regularly
arrayed as shown in FIG. 25a, the unit mask having halftone dots provided such that
the number thereof is varied so as to be reduced from the periphery toward the center
of the circle. When development is carried out after exposure, the negative resist
on non-exposed portions is removed in accordance with the exposure pattern, and projected
conical etching masks 17 are formed on the substrate 13 as shown in FIG. 24b.
[0149] Subsequently, the etching mask is etched back by reactive ion etching (RIE) as shown
in FIG. 24c to form microneedles 14 having a desired height on the substrate 13 (etch
process). The materials for the resist layer 12 and substrate 13 and the etching environment
are adjusted so that the etching selectivity ratio, which is defined by dividing the
etching rate of the substrate 13 per unit time by the etching rate of the resist layer
12, is set from 1 or more to 10 or less, preferably from 1 or more to 5 or less.
[0150] If the etching selectivity ratio is larger than 11, the control accuracy for the
microneedle 14 is reduced. If the etching selectivity ratio is smaller than 1, a resist
layer 12 having an unnecessarily large thickness is to be formed, leading to lowered
manufacturing efficiency.
[0151] Accordingly, the thickness of the resist layer 12 formed in the above-mentioned process
is set to a value defined by dividing the height of the microneedle manufactured by
a predetermined etching selectivity ratio.
[0152] Upon completion of the etching process, the etching masks 17 are completely removed
as shown in FIG. 24d, thereby providing a microneedle array 11 in which projected
microneedles 14 having a desired height are formed on the surface of the substrate
13.
[0153] The method of manufacturing a microneedle in this embodiment enables to manufacture
the microneedle array 11 with a far less number of steps than in the prior art by
using a stable substrate such as silicon.
[0154] If a thick resist layer 12 is formed using dip coating or an application method,
the etch-back etching rate can be set to a relatively low range of 1 or more to 10
or less in the etching process. Consequently, microneedles may be manufactured with
highly controlled precision.
[0155] Further, by transcribing the microneedle array 11 of this embodiment onto a resin
or metal material 18 as shown in FIG. 24e, a replica mold 19 for manufacturing a microneedle
may be readily manufactured as shown in FIG. 24f. In such a manner, the replica mold
for manufacturing the microneedle can be manufactured by a relatively small number
of steps by selecting an optimum material. Any method may be used for transcription
that is used in the prior art such as plating, a resin process or a ceramic process.
Further, by processing a biocompatible material using the above-mentioned replica
mold, a microneedle patch of the invention can be manufactured. Also, if a microneedle
is manufactured to have a hole inside and the amount of use of the biocompatible material
is adjusted, a microneedle in a single body that is not integrated with a base and
is able to be used for an injection syringe can be manufactured.
[0156] Although the microneedle array 11 is manufactured by using the negative resist in
this embodiment, if a positive resist is used in place of the negative resist, a microneedle
formed of the material of the substrate 13 can be provided through an etching process.
Accordingly, it is possible to manufacture the microneedles made of a more stable
material than a photosensitive material with a fewer steps and to directly manufacture
a microneedle patch using the microneedle.
[0157] Although the embodiments of the invention have been described above, the technical
scope of the invention is not limited to the above-mentioned embodiments, and various
modifications are possible within a range not departing from the spirit of the invention.
[0158] For example, the resist layer is exposed using a halftone dot mask or a gray scale
mask in the processes of exposure and development in the above-mentioned embodiments.
However, in place of the above-mentioned masks, the resist layer may be exposed by
multiple exposure of the laser beam depending on an integrated exposure value with
digitally adjusted exposure value by laser scanning based on the stereoscopic shape
of the microneedle to be manufactured.
[0159] The microneedle is formed in a circular conic shape or pyramidal shape in the above
embodiments, but the shape of the microneedle is not limited to these shapes. The
microneedle and replica mold may be manufactured by forming a microneedle having a
triangular pyramidal shape or polygonal pyramidal shape.
[0160] The coating layer is etched-back by reactive ion etching in the etching process in
the above embodiments, but the etching method is not limited thereto. For example,
any methods known in the art such as ion etching, ion-beam etching and reactive ion-beam
etching may be also used.
[0161] Although the microneedle patch is manufactured by injecting a molten biocompatible
material into the microneedle or the replica mold for manufacturing a microneedle
in the above embodiments, the microneedle patch may be manufactured by using commonly
used plastic molding methods such as compression molding and injection molding in
place of the methods described above.
Examples
Example 1
[0162] First, a silicon wafer was prepared as a substrate. The silicon wafer had crystal
orientation of (100) and a thickness of 525 mm. A chromium film with a thickness of
100 nm was formed on the silicon wafer by DC magnetron sputtering. The sputtering
pressure was 0.25 Pa and the input power was 1000W.
[0163] A positive resist (trade name: OFPR-50cp, manufactured by Tokyo Ohka Kogyo Co., Ltd.)
was applied to the chromium film as an etching mask in a thickness of 1 mm. A resist
pattern with an opening of 50 mm square was formed by photolithography. The chromium
film was etched with a mixed solution of perchloric acid and cerium (IV) ammonium
sulfate using the resist pattern as an etching mask to form a chromium pattern having
an opening of 50 mm square. After formation of the chromium pattern, the resist pattern
was removed with an organic solvent. The size of the opening of the chromium pattern
was measured to be 51 mm square (FIG. 4a).
[0164] The silicon wafer was subjected to anisotropic wet etching with an aqueous potassium
hydroxide solution at a concentration of 25% by weight and at a temperature of 90°C
by using the chromium pattern as an etching mask and by taking advantage of the difference
in the etching rate depending on the crystal orientation to form a recess on the surface
of the silicon wafer (FIG. 1b). After the wet etching, the chromium pattern was removed
with a mixed solution of perchloric acid and cerium (IV) ammonium sulfate. The shape
of the recess formed on the surface of the silicon wafer was observed with a scanning
electron microscope to have a depth of about 35 mm and an angle of opening at a deepest
portion of 70°. The angle of opening as used herein refers to an angle between opposed
sidewalls of a pyramidal shape.
[0165] A positive resist (trade name: OFRP-800, manufactured by Tokyo Ohka Kogyo Co., Ltd.)
was applied to the entire surface of the silicon wafer in a thickness of 50 mm. As
a result, the resist layer filled in the recess on the surface of the silicon wafer
had thickness distribution. The entire surface of the silicon wafer was etched by
ICP (inductively coupled plasma) etching using a fluorine-base gas until the resist
was completely removed. The etching selectivity ratio between the etching rates of
the resist and silicon was measured to be about 11.
[0166] When the sample subjected to etching was observed with a scanning electron microscope,
it was confirmed that a pyramidal needle with a bottom side length of 50 mm, a height
of about 350 mm and a point angle of about 8.2° was formed.
[0167] A nickel layer with a thickness of 300 nm was deposited by evaporation on the silicon
wafer on which the pyramidal needle was formed. A nickel layer with a thickness of
1 mm was formed by electroplating using the above-mentioned nickel layer as a seed
layer. Then, silicon was dissolved with an aqueous potassium hydroxide solution at
a concentration of 25% and at a temperature of 90°C to manufacture a replica mold
made of nickel according to the invention.
[0168] Transcription was performed to maltose, dextran, chitin-chitosan, or polylactic acid
by imprinting using the replica mold. It was confirmed that a needle with a bottom
side length of about 50 mm, a height of about 350 mm and a point angle of about 8.2°
was formed as formed on the silicon master mold by using any of the replication materials.
Example 2
[0169] An example of manufacturing a microneedle using an etching mask having a circular
dot pattern will be described.
[0170] First, a silicon wafer (thickness: 525 mm) was prepared as a substrate. A thick photoresist
for general purpose (trade name: AZ PLP, manufactured by Clariant Co.) was applied
to the silicon wafer as an etching mask in a thickness of 13 mm by spray coating.
Etching masks having a circular dot pattern with a diameter of 100 mm was formed by
photolithography.
[0171] Then, the etching masks were reflowed by heating the silicon wafer at 150°C for 30
minutes in a clean oven. The resist pattern after reflow had a cross-sectional shape
of a hemisphere and a thickness at the central portion of 20 mm.
[0172] Subsequently, the entire surface of the silicon wafer was etched by ICP (inductively
coupled plasma) etching using a fluorine-base gas until the resist pattern was completely
removed. As a result of measurement of the etching rates of the resist and silicon
substrate, it was found that the etching selectivity ratio of the silicon to the etching
mask was about 11.
[0173] The silicon wafer subjected to etching was observed with a scanning electron microscope.
It was confirmed that a circular conical needle with a diameter of the base portion
of about 100 mm, a height of about 220 mm and a point angle of about 25° was formed.
Example 3
[0174] A microneedle was manufactured as in Example 2. It should be noted that a pyramidal
etching mask having a cross-shaped bottom part as shown in FIGS. 2a and 2b was used.
The shape of the bottom of the etching mask was a cross formed by allowing two lines
with a width of 40 mm and a length of 150 mm to intersect at right angles. The thickness
of the etching mask was 18 mm at maximum.
[0175] The silicon wafer subjected to etching was observed with a scanning electron microscope
as in Example 2. A pyramidal needle having a cross-shaped bottom part formed by allowing
two lines with a width of 40 mm and a length of 150 mm to intersect at right angles
and a height of about 200 mm was provided.
Example 4
[0176] A microneedle was manufactured as in Example 2. It should be noted that a circular
conical etching mask with a part of the circular bottom depressed as shown in FIGS.
3a and 3b. The shape of the bottom of the etching mask was formed by cutting a portion
with a width of about 10 mm and a length of about 10 mm from the periphery to the
center of a circle with a diameter of 100 mm. The thickness of the etching mask was
19 mm at maximum.
[0177] The silicon wafer subjected to etching was observed with a scanning electron microscope
as in Example 2. A circular conical needle having a bottom shape in which a portion
with a width of about 10 mm and a length of about 10 mm was cut from the periphery
to the center of a circle with a diameter of 100 mm and a height of 210 mm was provided.
Example 5
[0178] An example of manufacturing a hollow microneedle will be described.
[0179] A silicon wafer (thickness: 525 mm) was prepared as a substrate. A hole with a diameter
of 20 mm and a depth of 200 mm was provided by perpendicular deep etching on the silicon
wafer at a position corresponding to the center of an etching mask to be formed.
[0180] Then, a copper thin film with a thickness of 100 nm was deposited on the surface
of the substrate and on the wall of the hole by DC magnetron sputtering. The deposition
pressure was set to 0.25 Pa. The copper film was used as a seed layer for electroplating
performed in the next step. A copper film with a thickness of 300 mm was deposited
by electroplating to fill the hole. A copper sulfate bath (copper sulfate 80 g/L,
sulfuric acid 200 g/L) was used as the plating solution, the temperature of which
was set to room temperature.
[0181] The plated substrate was then subjected to planarization treatment by chemical mechanical
polishing until the surface of the substrate was exposed for planarizing the surface
roughness.
[0182] Then, formation of the etching mask pattern, reflow and etching were performed as
in Example 2.
[0183] Subsequently, copper filled in the hole was removed by immersing the substrate in
an ferric chloride solution (30% FeCl
3, 3% HCl) for 2 hours.
[0184] The needle formed had an outer shape of a circular conical shape with a bottom diameter
of about 100 mm and a height of about 175 mm having a hollow part with a diameter
of 20 mm and a depth of 155 mm at the center.
Example 6
[0185] An example of manufacturing a microneedle by transcription will be described.
[0186] The microneedle manufactured by using the silicon wafer in Example 2 was used as
a master mold. A nickel film with a thickness of 300 nm was deposited on the surface
of the master mold by evaporation. A nickel film with a thickness of 1 mm was formed
by electroplating using the nickel layer as a seed layer. Then, the silicon wafer
was dissolved with an aqueous potassium hydroxide solution with a concentration of
25 wt% at a liquid temperature of 90°C to manufacture a replica mold made of nickel.
[0187] Transcription was performed to maltose, dextran, chitin-chitosan, or polylactic acid
by imprinting using the replica mold. As a result, it was confirmed that a needle
similar to the master mold was formed with any of the materials.
Example 7
[0188] An example of adjusting the shape of the microneedle will be described.
[0189] A circular conical needle with a diameter of the bottom part of about 100 mm, a height
of about 220 mm and a point angle of about 25° was formed on a silicon wafer as in
Example 2.
[0190] Then, the needle was cleaned with oxygen plasma and hydrofluoric acid, followed by
isotropic etching of the needle by about 5 mm with plasma mainly composed of a fluorine-base
gas. By performing the isotropic etching, the shape of the needle was changed to a
diameter of the bottom part of about 90 mm, a height of about 200 mm and a point angle
of about 22°, that is sharpness of the needle was improved.
Industrial Applicability
[0191] The method of manufacturing a microneedle of the invention is applicable to medical
field as well as to various fields that require fine needles. For example, the method
of the invention is useful for manufacturing microneedles used in MEMS devices, medical
fields, drug formulation and cosmetics.
1. A method of manufacturing a microneedle
characterized by comprising the steps of:
forming an island etching mask having thickness distribution on a substrate; and
processing the substrate into a needle by taking advantage of a difference in etching
rates between the etching mask and the substrate.
2. The method of manufacturing the microneedle according to claim 1, characterized in that an array of etching masks is formed on the substrate.
3. The method of manufacturing the microneedle according to claim 1,
characterized by comprising the steps of:
providing a recess having depth distribution on the substrate; and
forming the island etching mask having thickness distribution so as to cover at least
a part of the recess.
4. The method of manufacturing the microneedle according to claim 3, characterized in that the etching mask is formed so as to cover the recess and a part of a periphery of
the recess.
5. The method of manufacturing the microneedle according to claim 3, characterized in that the etching mask is formed so as to cover an entire surface of the substrate including
the recess.
6. The method of manufacturing the microneedle according to claim 3, characterized in that an opening is provided at a position corresponding to the recess of the etching mask.
7. The method of manufacturing the microneedle according to claim 6, characterized in that the opening is formed so as to be displaced from the recess.
8. The method of manufacturing the microneedle according to claim 1,
characterized by comprising the steps of:
forming an island etching mask on the substrate;
deforming the etching mask so as to have thickness distribution; and
processing the substrate into a needle by taking advantage of the difference in etching
rates between the etching mask and the substrate.
9. The method of manufacturing the microneedle according to claim 8, characterized in that the island etching mask formed on the substrate is deformed so as to have thickness
distribution by allowing the etching mask to reflow.
10. The method of manufacturing the microneedle according to claim 8, characterized in that the island etching mask is formed on the substrate by ejecting a droplet prepared
by dissolving an etching mask material in a solvent or by ejecting a droplet prepared
by heating and melting the etching mask material, and the etching mask is deformed
so as to have thickness distribution by allowing the solvent to evaporate or by allowing
the etching mask material to solidify.
11. The method of manufacturing the microneedle according to claim 1,
characterized by comprising the steps of:
forming a hole on the substrate;
filling the hole with a filler;
forming the island etching mask having thickness distribution on a side of the substrate
where the hole is formed;
etching the substrate to process into a needle; and
removing the filler.
12. The method of manufacturing the microneedle according to claim 1,
characterized by comprising the steps of:
forming a non-penetrated hole on the substrate;
forming the island etching mask having thickness distribution on a side of the substrate
opposed to the side where the non-penetrated hole is formed; and
etching the substrate to process into a needle.
13. The method of manufacturing the microneedle according to claim 11, characterized in that the hole is a penetrated hole or a non-penetrated hole.
14. The method of manufacturing the microneedle according to claim 11 or 12, characterized in that a position of the etching mask is aligned with a position of the hole.
15. The method of manufacturing the microneedle according to claim 11 or 12, characterized in that a position of the etching mask is displaced from a position of the hole.
16. The method of manufacturing the microneedle according to claim 8, characterized in that the etching mask is formed into a shape having an inwardly depressed part at a periphery.
17. The method of manufacturing the microneedle according to claim 1, characterized in that an etching selectivity ratio defined by dividing the etching rate of the substrate
by the etching rate of the etching mask is set to 1 or more and 100 or less.
18. The method of manufacturing the microneedle according to claim 1, characterized in that an etching condition is changed so that an etching selectivity ratio is changed on
the way of etching.
19. The method of manufacturing the microneedle according to claim 1,
characterized by comprising the steps of:
forming a resist layer on the substrate;
exposing the resist layer with light using any one of exposure through a mask using
a halftone dot pattern, exposure through a mask using a gray scale pattern, multiple
laser exposure and inclined exposure;
developing the resist layer to form the island etching mask having thickness distribution
on the substrate; and
processing the substrate into a needle by taking advantage of the difference in etching
rates between the etching mask and the substrate.
20. The method of manufacturing the microneedle according to claim 1, characterized in that the etching is anisotropic etching.
21. The method of manufacturing the microneedle according to claim 20, characterized in that the anisotropic etching is ion etching, reactive ion etching, ion-beam etching or
reactive ion-beam etching.
22. The method of manufacturing the microneedle according to claim 1, characterized in that after the microneedle is formed the microneedle is' subjected to isotropic etching.
23. A method of manufacturing a replica mold for manufacturing a microneedle, characterized by comprising the step of performing transcription using the microneedle manufactured
by the method according to claim 1 as a master mold.
24. The method of manufacturing the replica mold for manufacturing the microneedle according
to claim 23, characterized in that the transcription is performed by using a plated metal, resin or ceramic.
25. A microneedle manufactured by the method according to claim 1.
26. A microneedle characterized in that it is manufactured by using the replica mold for manufacturing the microneedle manufactured
by the method according to claim 23.
27. The microneedle according to claim 26, characterized in that it is formed of a biocompatible material.